Aging skeletal muscle exhibits a marked decrease in regenerative capabilities, which is associated with fatty infiltration and the deposition of fibrous connective tissue. This fibrotic deposition is particularly harmful because it interferes with proper muscle contraction. While this phenomenon has been widely documented, the mechanisms underlying this fibrosis are still under investigation. Unlike aged muscle, young muscle does not develop permanent fibrosis. However, it does display transient collagen deposition after acute injury. An understanding of the molecular pathways that trigger this collagen accumulation in young muscle as well as their dysregulation with age will be important for the development of therapeutics to prevent the progression of this pathology. Several studies have linked fibrosis to increased signaling of the platelet-derived growth factor (PDGF) pathway. Recently, it was shown that PDGF receptor alpha (PDGFR?) signaling promotes proliferation and differentiation of a population of muscle-resident fibroadipogenic progenitors (FAPs), which have been hypothesized to contribute to accumulation of both fibrous connective tissue and fat in muscle with age. Our preliminary data suggest that PDGFR? signaling is upregulated in FAPs upon muscle injury and that changes in this signaling pathway may influence their fibrogenic differentiation potential. We hypothesize that PDGFR? signaling in FAPs is responsible for their activation during muscle regeneration and that overstimulation of this pathway causes increased fibrosis. We will examine this hypothesis by studying PDGFR? signaling during normal muscle regeneration and testing whether the stimulation and inhibition of the pathway affects the development of fibrosis, and how depletion of FAPs alters muscle regenerative capacity (Aim 1). We will examine how the levels of PDGFR? signaling change in muscle with age and we will investigate whether inhibiting signal transduction results in a reduction in fibrosis accumulation in aged muscle (Aim 2). Finally, we will explore the mechanisms by which the PDGFR? transcript is regulated (Aim 3). Our preliminary data suggest that multiple variants of the PDGFR? transcript are produced that that these variants may alter the ultimate expression of the PDGFR? protein. We will study how PDGFR? is regulated post-transcriptionally through an analysis of polyadenylation site selection. Through our examination of this newly-discovered population of FAPs, we aim to understand the mechanisms that guide their activation in healthy muscle to assess their role in the fibrotic pathology of aged muscle. Our investigation will both allow for the production of new experimental tools to study this population and lend insight into therapeutic strategies to prevent age-related fibrosis. This will have direct relevance to Veterans who are suffering from skeletal muscle injuries, injuries that have limited their functional capacity and that, to date, have no hope of further recovery. This will also be directly relevant to our aging Veteran population, many of whom experience decreasing muscle strength and increasing muscle stiffness, limiting their normal activities. Our goal is to develop a therapeutic approach to muscle tissue repair based upon a deep understanding of the basic stem cell biology and a firm commitment to the clinical/translational mission to improve the health and quality of life of Veterans whose function is limited by the lack of effective therapeutic options.